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Costamere Protein Expression and Tissue Composition of Rotator Cuff Muscle After Tendon Release in Sheep

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Costamere Protein Expression and Tissue Composition of Rotator Cuff Muscle After Tendon Release in Sheep Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep Ruoss, Severin ; Möhl, Christoph B ; Benn, Mario C ; von Rechenberg, Brigitte ; Wieser, Karl ; Meyer, Dominik C ; Gerber, Christian ; Flück, Martin Abstract: Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found theactivity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained un- changed. At 2 weeks after tendon release, muscle volume decreased by 17 cm from an initial 185 cm(3) , the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm(3) , contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decreaseof muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clini- cally, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. © 2017 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc.on behalf of the Orthopaedic Research Society. J Orthop Res. DOI: https://doi.org/10.1002/jor.23624 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-141096 Journal Article Published Version Originally published at: Ruoss, Severin; Möhl, Christoph B; Benn, Mario C; von Rechenberg, Brigitte; Wieser, Karl; Meyer, Do- minik C; Gerber, Christian; Flück, Martin (2018). Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep. Journal of Orthopaedic Research, 36(1):272-281. DOI: https://doi.org/10.1002/jor.23624 Costamere Protein Expression and Tissue Composition of Rotator Cuff Muscle After Tendon Release in Sheep Severin Ruoss ,1 Christoph B. Mohl,€ 1 Mario C. Benn,2 Brigitte von Rechenberg,2 Karl Wieser,3 Dominik C. Meyer,3 Christian Gerber,3 Martin Fluck€ 1 1Laboratory for Muscle Plasticity, Balgrist Campus, University of Zurich, Zurich, Switzerland, 2Vetsuisse Faculty, University of Zurich, Zurich, Switzerland, 3Department of Orthopaedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland Received 25 November 2016; accepted 24 May 2017 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.23624 ABSTRACT: Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found the activity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained unchanged. At 2 weeks after tendon release, muscle volume decreased by 17 cm3 from an initial 185 cm3, the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm3, contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decrease of muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clinically, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. ß 2017 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res Keywords: rotator cuff tear; fatty infiltration; atrophy; costamere; tenotomy Tears of rotator cuff (RC) tendons are frequent and degraded,10 as they are held in place by the costamere, a affect a large portion of the elderly population.1,2 structural protein complex that links the Z-line to the These tears lead to retraction, fat accumulation, and extracellular matrix.11 Therefore, longitudinal atrophy atrophy of the musculotendinous unit.3 To reestablish first requires disruption of the structural anchors (i.e., normal shoulder function, RC tendon tears are often the costameres) by specific Ca2þ-activated proteases12 to surgically repaired, and the degree of muscle atrophy release the respective sarcomeres. In fact, Z-line stream- and fat accumulation correlates with the probability of ing is observed after tendon release in the rat13 and after repair failure.4,5 Until recently, these tendon tear- spontaneous tendon tears in various human muscles.14 induced changes were considered irreversible.3,6 Thus, The main regulator of costamere turnover is focal it is important to characterize these alterations to find adhesion kinase (FAK), an integrin-associated phos- solutions for their prevention and treatment and allow photransfer kinase that is activated by phosphoryla- a successful recovery from a RC tear. tion on its tyrosine 397 site (pY397). It is Tendon release induces a broad range of adaptations mechanosensitive and reacts to altered loading of the in the muscle, with reduced muscle length most fre- muscle.15 Changes in protein concentrations of FAK quently described.7 Regulation of muscle length occurs and FAK-pY397 after reduced muscle loading, for by adding (longitudinal hypertrophy) or removing (longi- example, unloading of human m. vastus lateralis16 or tudinal atrophy) contractile material (i.e., sarcomeres) at tendon release of the rat m. soleus17 are well de- theendsofmyofibrils8 and it has been shown that scribed. However, it is currently unknown whether tendon release leads to a reduced number of sarcomeres FAK, FAK-pY397, and concomitant alterations in in series.9 Sarcomeres are tightly incorporated in costamere turnover are affected by RC tears. a myofibril and cannot simply be removed and/or Apart from early surgical repair, another treat- ment option, which has been described in sheep6 and rabbits,18 is weekly administration of the anabolic This is an open access article under the terms of the Creative steroid nandrolone decanoate, which prevented fat Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the accumulation when treatment was started with the original work is properly cited, the use is non-commercial and no onset of the tear. To our knowledge, the action of modifications or adaptations are made. anabolic steroids on the costamere is not yet de- Conflicts of interest: The authors declare that they have no scribed after tendon release. Nevertheless, nandro- competing interests. 2þ Grant sponsor: RESORTHO; Grant sponsor: Schweizerischer lone decreased cytosolic Ca in the mouse m. soleus Nationalfonds zur Forderung€ der Wissenschaftlichen Forschung; after hindlimb unloading.19 This may result in lower Grant number: 149786. Ca2þ-activated protease activity and thereby de- Correspondence to: Martin Fluck€ (T: þ41-44-510-73-50; E-mail: mfl[email protected]) creased costamere cleavage, which potentially explains protection from muscle loss.10,12,20 In the # 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. ovine model of RC tear, the reduction of total muscle JOURNAL OF ORTHOPAEDIC RESEARCH MONTH 2017 1 2 RUOSS ET AL. volume after tendon release did not differ with or Single Step Repair without nandrolone administration; although, fat The details of this procedure, which involves removal of the accumulation was prevented by nandrolone.6 This silicon wrap and reattachment of the greater tuberosity to its 6 model has been used to replicate chronic tears (e.g., original site, have been previously described. at 16–40 weeks)6,21,22 with high intramuscular fat content (around 50%; Goutallier stage 323). However, Sampling of Muscle Tissue Approximately 40 mg of tissue (0.02% of average PRE muscle early alterations of muscle volume and composition volume) was
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